The overall goals of this research project are (1) to determine whether, via disruption of cellular programming that occurs during pregnancy, exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases susceptibility to breast cancer, and (2) to further characterize the effects of TCDD on mammary epithelial cells. The basis for this project is a recent novel discovery that we have made; specifically, that when young adult mice are exposed to the pollutant TCDD during their first pregnancy, mammary gland differentiation is severely impaired. This defect results in a lack of milk production and an inability to sustain their offspring. We believe our preliminary data suggest that by blocking normal pregnancy-associated mammary differentiation, exposure to dioxins may disrupt the normal signaling that ultimately protects breast tissue from cancer. The hypothesis for the proposed studies is that exposure to TCDD during pregnancy increases susceptibility to breast cancer later in life via direct effects on mammary epithelial cells. The rationale for this hypothesis stems from a large database describing the protective effects of early pregnancy, and evidence that parity-induced protection from breast cancer is thought to involve changes in cell fate. We will test this hypothesis in the context of three specific aims. Studies conducted in Aim 1 will determine whether mice treated with TCDD during pregnancy demonstrate increased susceptibility to developing mammary tumors. In Aim 2, we will determine whether this increased susceptibility is due to direct effects on mammary epithelial cells or is a downstream consequence of an insult to a different tissue or cell type. Finally, in Aim 3 we will identify defects in regulatory pathways that control mammary epithelial cell proliferation and apoptosis and perform tumorigenicity assays using TCDD-treated SCp2 cells. Significance: This project takes a novel and innovative approach to studying the role of exogenous compounds in breast cancer. This work will not continue or advance an existing line of research. Instead, the research proposed in this grant will bring a new investigator to the field of breast cancer research, and will provide an opportunity to explore a novel discovery that may lead to a major advancement in the battle to eradicate breast cancer. Relevance in lay language: The findings from this study will provide novel information concerning how exposure to dioxins, common pollutants in the environment, influences susceptibility to breast cancer. Specifically, we hypothesize that exposure to dioxins does not cause cancer directly, but blocks the signals that drive cellular differentiation, setting the stage for a future carcinogenic insult to initiate cancer. This is an innovative idea and will foster a new direction in breast cancer research. [unreadable] [unreadable]